PROJECT SUMMARY Here, we seek funding to purchase a modern, robust CMOS imaging device to replace obsolete MSC794 CCD to allow users efficiently and reliably screening and accessing quality of NS and cryo-samples for both single particle and tomographic preparations. The MSC794 (1 1k CCD) device serving TecnaiG2 T12 at Sanford Burnham Prebys Medical Discovery Institute (SBP) has reached ?end of life? status, thus it is no longer supported by Gatan or FEI vendors. Here, we seek funds for replacing it with a modern and robust 4 4k CMOS device. The CMOS device will also eliminate the use of Kodak ISO-163 plates, which is the current high-resolution imaging media available for this cryo-T12 TEM. The upgrade carries a high benefit-cost ratio. Several reasons come together in making the MSC794 a low-efficiency imaging device. Of significance are the relatively low rates of successful completion for full data acquisition, extremely small field of view (1K 1K) and the low quality of images acquired. The use of film not only strains the TEM vacuum system due to frequent changes in cameras thus limiting the amount of data we can record from individual grids, it also strains the pneumatics of the T12 system leading to additional down time and loss of samples The availability of modern, robust and mature CMOS camera will transform this TEM into an efficient, high-quality and modern instrument for supporting and streamlining the screening and quality control of NIH-funded single-particle or tomography studies. It will also, as importantly provide a more efficient usage time on the Titan Krios, as grids/samples selected for data acquisition will be T12 screened. The revamped instrument (the T12 with a CMOS mounted on-axis) will support a wide range of research projects initiated by several investigators from SBP as well as researchers from Stanford University, UCSD, UCSF, UCSB, TSRI, Yale University, University of Vermont, UNC-Chapel Hill, and Yeshiva. All of the projects highlighted in this application employ 2D- projection-based imaging and reconstructions techniques, ranging from single receptors, to complex macromolecular assemblies to whole cell preparations. All these researchers are funded through NIH- supported grants to pursue a broad range of health-related studies in the areas of developmental biology, cancer, gene expression, innate immunity and infectious diseases. These projects are only representatives of a potentially much larger pool of projects that could greatly benefit from access to this dedicated, modern imaging device.